Chronic liver disease kills an estimated 1000 people in the US every year and is caused in 40 percent of cases, by the hepatitis C virus. This virus has a positive strand RNA as its genome and a highly error prone NS5B RNA-dependent RNA polymerase for genomic replication. As a consequence, HCV has rapidly evolved with six genotypes and more than 14 sub-genotypes. Great efforts have been made to develop effective direct acting antivirals (DAA), however, by focusing on genotype 1a, the most predominant in western countries, we have neglected about 30 percent of people infected with HCV and moreover, victims found in third world countries. The heterogeneity of the virus has clearly set limitations to the discovery of a pan-genotypic DAA. That being said, I propose that by understanding the differences in substrate recognition of the most divergent HCV NS3/4A protease, we can get one step closer to designing an inhibitor that satisfies two major properties: 1) the inhibitor must fit within the overall substrate envelope of all HCV NS3/4A protease; 2) the inhibitor must exhibit a very low susceptibility to drug resistance. To that end, crystal structures of the protease domain of HCV NS3/4A from various genotypes will be determined in complex with their natural substrates and inhibitors.